Cellular and Molecular Life Sciences CMLS

, Volume 61, Issue 21, pp 2695–2703

What’s new in the renin-angiotensin system?

Hijacking epidermal growth factor receptors by angiotensin II: new possibilities for understanding and treating cardiac hypertrophy


  • N. J. Smith
    • Department of PharmacologyUniversity of Melbourne
  • H. -W. Chan
    • Gene Transcription Laboratory and Molecular Endocrinology LaboratoryBaker Heart Research Institute
  • J. E. Osborne
    • Gene Transcription Laboratory and Molecular Endocrinology LaboratoryBaker Heart Research Institute
  • W. G. Thomas
    • Department of Biochemistry and Molecular BiologyMonash University
    • Department of Biochemistry and Molecular BiologyUniversity of Melbourne
    • Growth Control LaboratoryThe Peter MacCallum Cancer Institute
Multi-author Review

DOI: 10.1007/s00018-004-4244-3

Cite this article as:
Smith, N.J., Chan, H.-., Osborne, J.E. et al. CMLS, Cell. Mol. Life Sci. (2004) 61: 2695. doi:10.1007/s00018-004-4244-3


Activation of the type 1 angiotensin II receptor (AT1R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT1R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT1R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the ‘triple membrane-passing signalling’ paradigm of AT1R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how ‘hijacking’ of the EGFR might explain the ability of the AT1R to elicit the temporally and qualitatively diverse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy.

Key words.

Type 1 angiotensin II receptor (AT1R)transactivationEGFRmetalloproteaseHB-EGFcardiac hypertrophy

Copyright information

© Birkhäuser Verlag, Basel 2004